microRNA as a Maternal Marker for Prenatal Stress-Associated ASD, Evidence from a Murine Model

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism Spectrum Disorder (ASD) pathogenesis involves complex genetic and environmental factors.
• Prenatal stress exposure is a potential risk factor for ASD, with the serotonin transporter (SERT) gene's short allele mediating this association.
• The interplay between maternal SERT genotype and prenatal stress requires further investigation in relation to offspring neurodevelopment.

Purpose of the Study:

• To investigate the combined effects of prenatal stress and maternal SERT genotype on offspring behavior in a mouse model.
• To explore the association between these factors and maternal microRNA (miRNA) expression during pregnancy.
• To identify potential biomarkers for ASD subtypes.

Main Methods:

• A mouse model was used, with pregnant females categorized by genotype (wildtype or SERT heterozygous knockout) and stress exposure (chronic variable stress or control).
• Offspring behavior was assessed at postnatal day 60 using tests for social interaction, anxiety, and repetitive behaviors.
• Maternal blood samples were analyzed for miRNA expression profiles at embryonic day 21.

Main Results:

• Offspring from SERT heterozygous knockout mothers exposed to stress exhibited significantly reduced social preference, particularly males.
• These offspring also displayed increased grooming behavior, indicative of repetitive actions, again notably in males.
• Three specific miRNAs (mmu-miR-7684-3p, mmu-miR-5622-3p, mmu-miR-6900-3p) were differentially expressed in the blood of mothers with SERT heterozygous knockout genotype exposed to stress.

Conclusions:

• Maternal SERT genotype and prenatal stress interact to influence specific behavioral outcomes in offspring, suggesting a pathway to certain ASD-related phenotypes.
• Differentially expressed maternal miRNAs late in pregnancy may serve as potential biomarkers for identifying a specific subtype of ASD pathogenesis.
• This study highlights the importance of considering gene-environment interactions in understanding ASD etiology.